Respiratory System
Fatima Obeidat, MD
1
I. ATELECTASIS (COLLAPSE)
- Is loss of lung volume caused by inadequate expansion of
air spaces.
- It results in shunting of inadequately oxygenated blood
from pulmonary arteries into veins, thus giving rise to a
ventilation-perfusion imbalance and hypoxia.
- On the basis of the underlying mechanism , atelectasis is
classified into three forms
A. Resorption atelectasis. : Occurs when complete bronchial
obstruction prevents air from reaching distal airways. 2
- The air already present gradually becomes absorbed, and
alveolar collapse follows.
- Depending on the level of airway obstruction, an entire
lung, a complete lobe, or one or more segments may be
involved.
- The most common cause is complete obstruction of a
bronchus by a mucous or mucopurulent plug.
- This frequently occurs postoperatively but also may
complicate bronchial asthma, bronchiectasis, chronic
bronchitis, tumor, or foreign body aspiration, particularly in
children.3
B. Compression atelectasis. : passive or relaxation
atelectasis) :- Is usually associated with accumulation of
fluid, blood, or air within the pleural cavity, which
mechanically collapses the adjacent lung and this is a
frequent occurrence with :
a. Pleural effusion, caused most commonly by congestive
heart failure (CHF).
b. Leakage of air into the pleural cavity (pneumothorax)
c. Basal atelectasis resulting from the elevated position of
the diaphragm commonly occurs in bedridden patients, in
patients with ascites, 4
C. Contraction atelectasis.
- Contraction (or cicatrization) atelectasis
- Occurs when either local or generalized fibrotic changes in
the lung or pleura hamper expansion
NOTE:
- Atelectasis (except when caused by contraction) is
potentially reversible and should be treated promptly to
prevent hypoxemia and superimposed infection of the
collapsed lung.
5
Types of atelectasis
6
II. Acute lung injury- It encompasses a spectrum of bilateral pulmonary damage
(endothelial and epithelial), which can be initiated by
numerous conditions and it manifests as :
1. Acute onset of dyspnea,
2. Decreased arterial oxygen pressure (hypoxemia),
3. Bilateral pulmonary infiltrates on the chest radiograph,
4. Absence of clinical evidence of primary left-sided heart
failure
7
- Since the pulmonary infiltrates in acute lung injury are
usually caused by damage to the alveolar capillary
membrane, rather than by left-sided heart failure , such
accumulations constitute an example of noncardiogenic
pulmonary edema.
- Acute lung injury can progress to the more severe acute
respiratory distress syndrome,
8
Acute Respiratory Distress Syndrome
- Is a clinical syndrome caused by diffuse alveolar capillary
and epithelial damage and is characterized by:
a. Rapid onset of life-threatening respiratory insufficiency,
b. Severe arterial hypoxemia that is refractory to oxygen
therapy and may progress to multisystem organ failure.
Note: The histologic manifestation of ARDS in the lungs is
known as diffuse alveolar damage (DAD).
- ARDS can occur in a multitude of clinical settings and is
associated with either direct injury to the lung or indirect9
injury in the setting of a systemic process
Direct Lung Injury
I. Common Causes
1.Pneumonia
2. Aspiration of gastric contents
II. Uncommon Causes
1. Pulmonary contusion 2.Fat embolism
It should be recalled that respiratory distress syndrome
of the newborn is pathogenetically distinct; it is
caused by a primary deficiency of surfactant 10
• Indirect causes
I. common causes
1. Sepsis
2. Severe trauma with shock
II. Uncommon causes
1. Acute pancreatitis
2. Drug overdose
11
PATHOGENESIS
- The alveolar-capillary membrane is formed by two barriers: the
endothelium and alveolar epithelium.
- In ARDS, the integrity of this barrier is compromised by
endothelial or epithelial injury, or, more commonly, both.
- The acute consequences of damage to the alveolar capillary
membrane include :
a. Increased vascular permeability and alveolar flooding,
b. widespread surfactant abnormalities caused by damage to type II
pneumocytes
- Recent work suggests that in ARDS, lung injury is caused by an
imbalance of pro-inflammatory and anti-inflammatory mediators.12
a. 30 minutes after an acute insult, there is increased
synthesis of interleukin 8 (IL-8), a potent neutrophil
chemotactic factor released by pulmonary macrophages.
b. Release of mediators, such as IL-1 and tumor necrosis
factor (TNF), leads to endothelial activation and activation
of neutrophils in pulmonary capillaries.
- Neutrophils are thought to have an important role in the
pathogenesis of ARDS
- Histologic examination of lungs early in the disease
process shows increased numbers of neutrophils within
the vascular space, the interstitium, and the alveoli13
- Neutrophils release a variety of products (, oxidants,
proteases,or, leukotrienes) that cause damage to the
alveolar epithelium and endothelium.
- Combined assault on the endothelium and epithelium
perpetuates vascular leakiness and loss of surfactant that
render the alveolar unit unable to expand.
- The destructive forces can be counteracted by endogenous
, antioxidants, and anti-inflammatory cytokines (e.g., IL-10)
- In the end, it is the balance between the destructive and
protective factors that determines the degree of tissue
injury and clinical severity of ARDS. 14
• MORPHOLOGY
I. Acute phase of ARDS, Microscopic examination reveals:
1. Capillary congestion
2. Necrosis of alveolar epithelial cells,
3. Interstitial and intra-alveolar edema and hemorrhage
4. With sepsis collections of neutrophils in capillaries
5. The most characteristic finding is hyaline membranes,
particularly lining the distended alveolar ducts
- Such membranes consist of fibrin-rich edema fluid
admixed with remnants of necrotic epithelial cells. 15
ARDS
16
Note: The picture is similar to that seen in respiratory
distress syndrome in the newborn .
In the organizing stage,
1. Vigorous proliferation of type II pneumocytes occurs in an
attempt to regenerate the alveolar lining.
2. Resolution is unusual; more commonly, there is
organization of the fibrin exudates, with resultant intra-
alveolar fibrosis.
3.Marked thickening of the alveolar septa ensues, caused by
proliferation of interstitial cells and deposition of collagen.. 17
• Clinical Features
- Approximately 85% of patients develop the clinical
syndrome of ARDS within 72 hours of the initiating insult.
- With improvements in supportive therapy, the mortality
rate has decreased from 60% to 40% in the last decade.
-Predictors of poor prognosis include
1. Advanced age
2. Underlying bacteremia (sepsis )
3. Development of multisystem (cardiac, renal, or hepatic)
failure. 18
- If the patient survive the acute stage, diffuse interstitial
fibrosis may occur, with continued compromise of
respiratory function.
- However, in most patients who survive the acute insult
and are spared the chronic sequelae, normal
respiratory function returns within 6 to 12 months
19
III. OBSTRUCTIVE VERSUS RESTRICTIVE
PULMONARY DISEASES
The major diffuse obstructive disorders are
1. Emphysema,
2. Chronic bronchitis,
3. Bronchiectasis,
4. Asthma.
Note: Expiratory obstruction may result either from anatomic
airway narrowing,in asthma, or from loss of elastic recoil,
characteristic of emphysema 20
• OBSTRUCTIVE LUNG (AIRWAY) DISEASES
- Have distinct clinical and anatomic characteristics but
overlaps between emphysema, bronchitis, and asthma are
common.
1. The definition of emphysema is morphologic, whereas
chronic bronchitis is defined on the basis of clinical
features
2.The anatomic distribution is partially different; chronic
bronchitis initially involves the large airways, whereas
emphysema affects the acinus.21
- Although chronic bronchitis may exist without emphysema,
and almost pure emphysema may occur (particularly in
patients with inherited α1-antitrypsin deficiency) the two
diseases usually coexist.
- This is almost certainly because the major cause-cigarette
smoking, especially long-term, heavy tobacco exposure-is
common to both disorders
- Due to their propensity to coexist, emphysema and chronic
bronchitis often are clinically grouped together under the
rubric of chronic obstructive pulmonary disease (COPD).
22
1.Emphysema- Characterized by abnormal permanent enlargement of the
air spaces distal to the terminal bronchioles, accompanied
by destruction of their walls without significant
- Is classified according to its anatomic distribution within
the lobule;
- The acinus is the structure distal to terminal bronchioles,
and a cluster of three to five acini is called a lobule
- There are four major types of emphysema:
(1) centriacinar, (2) panacinar, (3) distal acinar, (4) irregular. 23
-Only the first two types cause significant airway obstruction,
- Centriacinar emphysema being about 20 times more
common than panacinar disease.
1.Centriacinar (Centrilobular) Emphysema
- The distinctive feature of centriacinar (centrilobular)
emphysema is the pattern of involvement of the lobules:
- The central or proximal parts of the acini, formed by
respiratory bronchioles, are affected, while distal alveoli
are spared
24
Emphysema
25
- Thus, both emphysematous and normal air spaces exist
within the same acinus and lobule
- The lesions are more common and severe in the upper
lobes, particularly in the apical segments.
- In severe centriacinar emphysema the distal acinus also
becomes involved, and thus, the differentiation from
panacinar emphysema becomes difficult.
- This type of emphysema is most commonly seen as a
consequence of cigarette smoking in people who do not
have congenital deficiency of α1-antitrypsin26
2. Panacinar (Panlobular) Emphysema
- The acini are uniformly enlarged, from the level of the respiratory
bronchiole to the terminal blind alveoli
- It occurs more commonly in the lower lung zones
- Is the type of emphysema that occurs in α1-antitrypsin deficiency.
3. Distal Acinar (Paraseptal) Emphysema
- The proximal portion of the acinus is normal but the distal part is
primarily involved.
- The emphysema is more striking adjacent to the pleura and along
the lobular connective tissue septa
27
- It occurs adjacent to areas of fibrosis or scarring and is
usually more severe in the upper half of the lungs.
- The characteristic finding is the presence of multiple,
contiguous, enlarged air spaces ranging in diameter from
less than 0.5 mm to more than 2.0 cm, sometimes forming
cystic structures that, with progressive enlargement, are
referred to as bullae.
• The cause of this type of emphysema is unknown; it is
seen most often in cases of spontaneous pneumothorax in
young adults.
28
PATHOGENESIS
- Exposure to toxic substances such as tobacco smoke and inhaled
pollutants induces ongoing inflammation with accumulation of
neutrophils, macrophages and lymphocytes in the lung.
- Elastases, cytokines (including IL-8) and oxidants are released
causing epithelial injury and proteolysis of the extracellular matrix
(ECM) and unless checked by antielastases (e.g., α1-antitrypsin)
and antioxidants, the c inflammation and ECM proteolysis
continues.
- More than 80% of patients with congenital α1-antitrypsin
deficiency develop symptomatic panacinar emphysema, which
occurs at an earlier age and with greater severity if the affected
person smokes . 29
- There is marked individual variation in susceptibility to the
development of emphysema/COPD.
- Multiple genetic factors control the response to injury after
smoking.
a. The TGFB gene exhibits polymorphisms that influence
susceptibility to the development of COPD by regulating
the response of mesenchymal cells to injury.
- With certain polymorphisms, mesenchymal cell response
to TGF-β signaling is reduced, which in turn results in
inadequate repair of elastin injury caused by inhaled toxins30
b.Matrix metalloproteinases (MMPs), especially MMP-9 and
MMP-12, have a pathogenic role in emphysema
- MMP-9 gene polymorphisms and higher levels of both
MMP-9 and MMP-12 have been found in some
emphysema patients
- Complex interactions between inflammatory mediators,
cell signaling and inappropriate activation of repair
mechanisms may result in different diseases: tissue
destruction without fibrosis (emphysema) or interstitial
fibrosis 31
NOTE; Recent data indicate that mesenchymal cell response may
be a key factor in determining which of these two processes
ensues.
- In emphysema there is loss of not only epithelial and endothelial
cells but also mesenchymal cells, leading to lack of extracellular
matrix, the scaffolding upon which epithelial cells would have
grown.
- Thus, emphysema can be thought of as resulting from insufficient
wound repair.
- By contrast, patients with fibrosing lung diseases have excessive
myofibroblastic or fibroblastic response to injury, leading to
unchecked scarring.32
MORPHOLOGY
- Panacinar emphysema: produces pale, voluminous lungs
that often obscure the heart when the anterior chest wall is
removed at autopsy.
- The macroscopic features of centriacinar emphysema are
less impressive: The lungs are a deeper pink than in
panacinar emphysema and less voluminous, unless the
disease is well advanced.
- In centriacinar emphysema the upper two thirds of the
lungs are more severely affected than the lower lungs.
33
Histologic examination reveals :
1.Destruction of alveolar walls without fibrosis, leading to
enlarged air spaces
2. The number of alveolar capillaries is diminished.
3. Terminal and respiratory bronchioles may be deformed
because of the loss of septa
4. With the loss of elastic tissue in the surrounding alveolar
septa, radial traction on the small airways is reduced.
- As a result, they tend to collapse during expiration-an
important cause of chronic airflow obstruction in severe
emphysema.
.
34
Emphysema
35
Clinical Features
- Dyspnea usually is the first symptom; it begins insidiously but is
steadily progressive.
- In patients with underlying chronic bronchitis or chronic asthmatic
bronchitis, cough and wheezing may be the initial complaints.
- Weight loss is common and may be so severe as to suggest a
hidden malignant tumor.
- The classic presentation in emphysema with no "bronchitic"
component is one in which the patient is barrel-chested and
dyspneic, with obviously prolonged expiration, sitting forward in a
hunched-over position, attempting to squeeze 36
the air out of the lungs with each expiratory effort.
- Dyspnea and hyperventilation are prominent, so that until very late
in the disease, gas exchange is adequate and blood gas values
are relatively normal.
- Because of prominent dyspnea and adequate oxygenation of
hemoglobin, these patients sometimes are called "pink puffers."
- At the other extreme of the clinical presentation in emphysema is a
patient who also has pronounced chronic bronchitis and a history
of recurrent infections with purulent sputum.
- Dyspnea usually is less prominent, with diminished respiratory
drive, so the patient retains carbon dioxide
37
, becomes hypoxic, and often is cyanotic.
- For reasons not entirely clear, such patients tend to be obese-
hence the designation "blue bloaters” and Often they seek
medical help after the onset of CHF (cor pulmonale) and
associated edema
- In all cases, secondary pulmonary hypertension develops
gradually, arising from both hypoxia-induced pulmonary vascular
spasm and loss of pulmonary capillary surface area from alveolar
destruction.
- Death from emphysema is related to either pulmonary failure, with
respiratory acidosis, hypoxia, and coma, or right-sided heart
failure (cor pulmonale). 38
Conditions Related to Emphysema• Several conditions resemble emphysema only superficially but
nevertheless are (inappropriately) referred to as such:
I. Compensatory emphysema : Compensatory dilation of alveoli in
response to loss of lung substance such as occurs in residual
lung after surgical removal of a diseased lung or lobe.
II. Obstructive overinflation:-
- Refers to the condition in which the lung expands because air is
trapped within it.
- A common cause is subtotal obstruction by a tumor or foreign
object.
- Can be a life-threatening 39
III. Bullous emphysema
- Refers to any form of emphysema that produces large
subpleural blebs or bullae (spaces greater than 1 cm in
diameter in the distended state)
- Such blebs represent localized accentuations of one of the
four forms of emphysema; most often the blebs are
subpleural, and on occasion they may rupture, leading to
pneumothorax.
40
Bullous emphysema
41
Bullous emphysema
42
IV. Mediastinal (interstitial) emphysema
- Is the condition resulting when air enters the connective
tissue of the lung, mediastinum, and subcutaneous tissue.
- This may occur :
a. Spontaneously with a sudden increase in intra-alveolar
pressure (as with vomiting or violent coughing) resulting in
a tear, with dissection of air into the interstitium
b. In children ldren with whooping cough
c. patients on respirators who have partial bronchiolar
obstruction 43
d. Persons who suffer a perforating injury ( a fractured rib).
- When the interstitial air enters the subcutaneous tissue, the
patient may blow up like a balloon, with marked swelling of
the head and neck and crackling crepitation all over the
chest.
- In most instances, the air is resorbed spontaneously after
the site of entry is sealed.
44
2. Chronic Bronchitis- Is common among cigarette smokers and urban dwellers
- The diagnosis of chronic bronchitis is made on clinical grounds: it
is defined by the presence of a persistent productive cough for at
least 3 consecutive months in at least 2 consecutive years.
- In early stages of the disease, the productive cough raises mucoid
sputum, but airflow is not obstructed.
- Some patients with chronic bronchitis may demonstrate
hyperresponsive airways with bronchospasm and wheezing.
- A subset of bronchitic patients, especially heavy smokers,
develop chronic outflow obstruction, usually with associated
emphysema45
PATHOGENESIS
- The distinctive feature of chronic bronchitis is
hypersecretion of mucus, beginning in the large airways.
- Although the single most important cause is cigarette
smoking, other air pollutants, such as sulfur dioxide and
nitrogen dioxide, may contribute.
- These environmental irritants induce hypertrophy of
mucous glands in the trachea and main bronchi, leading to
a marked increase in mucin-secreting goblet cells in the
surface epithelium of smaller bronchi and bronchioles46
- These irritants cause inflammation with infiltration of CD8+
lymphocytes, macrophages, and neutrophils and In
contrast with asthma, there are no eosinophils
- The morphologic basis of airflow obstruction in chronic
bronchitis is more peripheral and results from
1. Small airway disease, induced by goblet cell metaplasia
with mucous plugging of the bronchiolar lumen,
inflammation, and bronchiolar wall fibrosis,
- small airway disease (also known as chronic bronchiolitis)
is an important component of early and mild airflow
obstruction 47
2. coexistent emphysema: Causes significant airflow
obstruction
- Many of the respiratory epithelial effects of environmental
irritants (e.g., mucus hypersecretion) are mediated by local
release of T cell cytokines such as IL-13.
- The transcription of the mucin gene MUC5AC in bronchial
epithelium and the production of neutrophil elastase are
increased as a result of exposure to tobacco smoke.
- Microbial infection often is present but has a secondary
role, chiefly by maintaining the inflammation and
exacerbating symptoms. 48
MORPHOLOGY
Gross:
- The mucosal lining of the larger airways usually is hyperemic and
swollen by edema fluid and often covered by a layer of mucinous
or mucopurulent secretions.
- The smaller bronchi and bronchioles may be filled with secretions.
On histologic examination,
1- The diagnostic feature of chronic bronchitis in the larger bronchi
is enlargement of the mucus-secreting glands
2.- The magnitude of the increase in size is assessed by the ratio of
the thickness of the submucosal gland layer to that of the
bronchial wall (the Reid index-normally 0.4). 49
Chronic bronchitis
50
2.Mononuclear cells admixed with neutrophils, are frequently
present in variable density in the bronchial mucosa .
3. Small airway disease, characterized by
a. Goblet cell metaplasia,with mucous plugging
b., Inflammation, and fibrosis, is also present .
c. In the most severe cases, there may be complete obliteration of
the lumen as a consequence of fibrosis (bronchiolitis obliterans).
It is the submucosal fibrosis that leads to luminal narrowing and
airway obstruction.
4. Changes of emphysema often co-exist
51
Clinical Features
- In patients with chronic bronchitis, a prominent cough and the
production of sputum may persist indefinitely without ventilatory
dysfunction
- Some patients develop significant COPD with outflow obstruction
and this clinical syndrome is accompanied by hypercapnia,
hypoxemia, and cyanosis (hence the term "blue bloaters").
- With progression, chronic bronchitis is complicated by pulmonary
hypertension and cardiac failure . Recurrent infections and
respiratory failure are constant threats.
52
3. Asthma- Asthma is a chronic inflammatory disorder of the airways
that causes recurrent episodes of wheezing,
breathlessness, chest tightness, and cough, particularly at
night and/or early in the morning.
The hallmarks of the disease are
a. intermittent and reversible airway obstruction,
b. chronic bronchial inflammation with eosinophils,
c. bronchial smooth muscle cell hypertrophy and
hyperreactivity,
d. and increased mucus secretion. 53
- Some of the stimuli that trigger attacks in patients would
have little or no effect in persons with normal airways.
- Many cells play a role in the inflammatory response, in
particular eosinophils, mast cells, macrophages,
lymphocytes, neutrophils, and epithelial cells.
-Asthma may be categorized into
1.Atopic (evidence of allergen sensitization, often in a patient
with a history of allergic rhinitis, eczema) and
2. Nonatopic.
54
• PATHOGENESIS
- The major etiologic factors of asthma are :
a. Genetic predisposition to type I hypersensitivity (atopy),
b. acute and chronic airway inflammation,
c. and bronchial hyperresponsiveness to a variety of stimuli.
- The inflammation involves many cell types and numerous
inflammatory mediators, but the role of type 2 helper T (TH2) cells
may be critical to the pathogenesis of asthma.
The classic atopic form of asthma
a. is associated with an excessive TH2 reaction against
environmental antigens55
b. Cytokines produced by TH2 cells account for most of the features
of asthma
1-IL-4 stimulates IgE production
2., IL-5 activates eosinophils,
3. and IL-13 stimulates mucus production and also promotes IgE
production by B cells.
c. IgE coats submucosal mast cells, which, on exposure to allergen,
release granule contents and this induces two waves of reaction:
an early (immediate) phase and a late phase
The early reaction is dominated by
a. bronchoconstriction,
b. increased mucus production 56
c.vasodilation.
- Bronchoconstriction is triggered by direct stimulation of
subepithelial vagal receptors.
The late-phase reaction
a. consists of inflammation, with activation of eosinophils,
neutrophils, and T cells.
b. epithelial cells are activated to produce chemokines that promote
recruitment of more TH2 cells and eosinophils (including eotaxin,
a potent chemoattractant and activator of eosinophils), as well as
other leukocytes, thus amplifying the inflammatory reaction.
- Repeated bouts of inflammation lead to structural changes in the
bronchial wall, collectively referred to as airway remodeling57
- These changes include:
a. hypertrophy of bronchial smooth muscle
b. and mucus glands,
c. deposition of subepithelial collagen,
- These changes may occur as early as several years
before initiation of symptoms.
Note:
- Asthma is a complex genetic disorder in which multiple
susceptibility genes interact with environmental factors to
initiate the pathologic reaction. 58
- There is significant variation in the expression of these genes and
in the combinations of polymorphisms that effect the immune
response or tissue remodeling.
1. One susceptibility locus is on the long arm of chromosome 5
(5q), where several genes involved in regulation of IgE synthesis
and mast cell and eosinophil growth and differentiation map and
the genes at this locus include
a. IL13 (genetic polymorphisms linked with susceptibility to the
development of atopic asthma)
b.CD14(single-nucleotide polymorphisms associated with
occupational asthma),
c. class II HLA alleles (tendency to produce IgE antibodies)59
d.- β2-adrenergic receptor gene,
e. IL-4 receptor gene (atopy, total serum IgE level, and asthma).
2. Another important locus is on 20q where ADAM-33 that regulates
proliferation of bronchial smooth muscle and fibroblasts is located;
this controls airway remodeling.
Note:
- Upregulation of various chitinase enzymes has been shown
to be important in TH2 inflammation and severity of asthma; high
serum YKL-40 levels (a chitinase family member with no
enzymatic activity) correlate with the severity of asthma.
60
Types of Asthma
1.Atopic Asthma
a. the most common type of asthma,
b. usually beginning in childhood,
c. is a classic example of type I IgE-mediated
hypersensitivity reaction
d. A positive family history of atopy and/or asthma is
common,
e. asthmatic attacks are often preceded by allergic rhinitis,
urticaria, or eczema. 61